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——口水太多怎么办？打一针Xeomin，可治疗成人流涎症

2018年7月4日，Merz Neuroscience是Merz北美公司的旗下公司，专注于开发创新方案，解决神经科学领域存在的未满足医疗需求。近日，该公司宣布，美国食品和药物管理局（FDA）已批准神经毒素产品Xeomin（incobotulinumtoxinA，A型复合游离肉毒毒素），用于成人患者治疗慢性（长期）流涎症（chronic sialorrhea，即唾液过多、大量流口水）。

FDA通过优先审评程序对Xeomin进行了审查。此次批准，使Xeomin成为美国市场首个也是唯一一个获批该适应症的神经毒素产品。慢性流涎症也是Xeomin在美国获批的第4种神经适应症。

流涎症（sialorrhea）主要表现为流口水较多，这是神经系统疾病患者的常见症状，包括帕金森病（PD）、肌萎缩侧索硬化症（ALS）、脑性瘫痪（CD）以及发生了脑卒中的患者。该病可能是由于吞咽问题或面部肌肉控制问题导致口腔内难以保持唾液。

Xeomin是一种处方药，通过注射入肌肉或腺体内发挥作用。在美国市场，Xeomin于2010年首次获批治疗成人肌张力障碍、眼睑痉挛（既往已接受艾尔建保妥适Botox[onabotulinumtoxinA，A型肉毒毒素]治疗的眼睑痉挛），之后在2015年获批治疗成人上肢痉挛。

Xeomin的获批，是基于一项随机、双盲、安慰剂对照、多中心III期临床的数据。该研究入组了184例流涎症成人患者，36例患者接受安慰剂治疗，74例患者接受75个单位Xeomin治疗，74例患者接受100个单位Xeomin治疗。数据显示，该研究成功达到了共同主要终点：在治疗第4周，与安慰剂注射组相比，100个单位Xeomin注射组在无刺激唾液流率（uSFR）和总体改变印象量表（GICS）相对注射前基线均表现出统计学意义的显著改善（分别为：p=0.004，p=0.002）。GICS是临床医生常用的一种评估神经系统疾病治疗的评分系统。该研究中，不良事件整体发生率方面，安慰剂组和治疗组相似，没有发生新的或未预料到的不良事件。

Merz北美公司副总裁兼神经科学负责人Kevni O'Brien表示，直到现在，还没有一种获FDA批准治疗这种疾病的药物。Xeomin的获批标志着一个重要的里程碑，将解决美国地区遭受慢性流涎症困扰的超过60万成人患者中存在的未满足医疗需求，践行了Merz公司致力于改善运动障碍患者生活的承诺。

 

原文出处：FDA APPROVES XEOMIN® (INCOBOTULINUMTOXINA) FOR ADULT PATIENTS WITH SIALORRHEA

 

 

 

Xeomin

Generic Name: incobotulinumtoxinA
Dosage Form: powder, lyophilized, for solution

Medically reviewed on July 1, 2018

 

WARNING: DISTANT SPREAD OF TOXIN EFFECT

Postmarketing reports indicate that the effects of Xeomin and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses [see Warnings and Precautions (5.1)].

 

 

 

 

 

 

 

 

 

Indications and Usage for XeominChronic Sialorrhea

Xeomin (incobotulinumtoxinA) is indicated for the treatment of chronic sialorrhea in adult patients.

Upper Limb Spasticity

Xeomin (incobotulinumtoxinA) is indicated for the treatment of upper limb spasticity in adult patients.

Cervical Dystonia

Xeomin (incobotulinumtoxinA) is indicated for the treatment of adults with cervical dystonia in both botulinum toxin-naïve and previously treated patients.

Blepharospasm

Xeomin (incobotulinumtoxinA) is indicated for the treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (Botox).

Glabellar Lines

Xeomin (incobotulinumtoxinA) is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.

 

 

Xeomin Dosage and AdministrationInstructions for Safe Use

The potency Units of Xeomin (incobotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of Xeomin cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11)]. Reconstituted Xeomin is intended for intramuscular or intra-salivary gland injection only.

The recommended maximum cumulative dose for any indication should not exceed 400 Units in a treatment session.

 

 

 

 

Chronic Sialorrhea

Xeomin is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The recommended total dose per treatment session is 100 Units. The dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 1).

Figure 1: Glands for Injection in Chronic Sialorrhea

M = Masseter

Use the following guidelines if locating salivary glands using anatomic landmarks:

1)

To inject the parotid gland, find the midpoint on the line connecting the tragus and mandible angle (Site A and B, respectively, Figure 1), approximately at the height of the ear lobe. Deliver the injection one finger breadth anterior to this site (Star 1, Figure 1).

2)

To inject the submandibular gland, find the midpoint between the angle of the mandible and the tip of the chin (Site B and C, respectively, Figure 1). Deliver the injection one finger breadth medial to the inferior surface of the mandible at this site (Star 2, Figure 1).

Table 1: Dosing by Gland for Treatment of Chronic Sialorrhea
Gland(s)	Units Per Side	Total
Parotid gland(s)	30 Units	60 Units
Submandibular gland(s)	20 Units	40 Units
Both Glands	50 Units	100 Units

The concentration used in the clinical study after reconstitution is 5 Units/0.1mL. The timing for repeat treatment should be determined based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

Upper Limb Spasticity

The dosage, frequency, and number of injection sites should be tailored to the individual patient based on the size, number, and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient's response to previous treatment, and adverse event history with Xeomin. The frequency of Xeomin treatments should be no sooner than every 12 weeks. In spasticity patients not previously treated with botulinum toxins, initial dosing should begin at the low end of the recommended dosing range and titrated as clinically necessary. Most patients in clinical studies were retreated between 12-14 weeks.

Table 2: Xeomin Dosing by Muscle for Treatment of Upper Limb Spasticity
Clinical Pattern Muscle	Units (Range)	Number of injection sites per muscle
Clenched Fist
Flexor digitorum superficialis	25 Units-100 Units	2
Flexor digitorum profundus	25 Units-100 Units	2
Flexed Wrist
Flexor carpi radialis	25 Units-100 Units	1-2
Flexor carpi ulnaris	20 Units-100 Units	1-2
Flexed Elbow
Brachioradialis	25 Units-100 Units	1-3
Biceps	50 Units-200 Units	1-4
Brachialis	25 Units-100 Units	1-2
Pronated Forearm
Pronator quadratus	10 Units-50 Units	1
Pronator teres	25 Units-75 Units	1-2
Thumb-in-Palm
Flexor pollicis longus	10 Units-50 Units	1
Adductor pollicis	5 Units-30 Units	1
Flexor pollicis brevis/Opponens pollicis	5 Units-30 Units	1

Figure 2: Muscles Involved In Adult Upper Limb Spasticity

Cervical Dystonia

The recommended initial total dose of Xeomin for cervical dystonia is 120 Units. In a placebo-controlled trial utilizing initial Xeomin doses of 120 Units and 240 Units, no meaningful difference in effectiveness was demonstrated between the doses [see Clinical Studies (14.3)]. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the Xeomin dose.

In the treatment of cervical dystonia, Xeomin is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.3)]. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections.

The frequency of Xeomin repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.3)].

Blepharospasm

The recommended initial total dose of Xeomin should be the same dose as the patient's previous treatment of onabotulinumtoxinA (Botox), although responses to Xeomin and onabotulinumtoxinA (Botox) may differ in individual patients. In a placebo-controlled trial in which patients were dosed with the same number of Units as they had received previously with onabotulinumtoxinA (Botox), the mean dose per eye was about 33 Units (range 10 Units-50 Units), and the mean number of injections per eye was 6. The maximum dose per eye in the controlled trials was 50 Units, with a range of 10 Units-50 Units. In the controlled trial, few patients received a total dose of greater than 75 Units.

If the previous dose of Botox is not known, the initial dose of Xeomin should be between 1.25 Units-2.5 Units/injection site.

The total initial dose of Xeomin in both eyes should not exceed 70 Units (35 Units/eye).

The number and location of injection sites should be based on the severity of blepharospasm, and previous dose and response to onabotulinumtoxinA (Botox) injections. Subsequent dosing should be tailored to the individual patient, based on response, up to a maximum dose of 35 Units per eye [see Clinical Studies 14.4]. Xeomin dosing has not been established in patients with blepharospasm who have not been previously treated with onabotulinumtoxinA (Botox).

The frequency of Xeomin repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.4)].

Glabellar Lines

The total recommended Xeomin dose is 20 Units per treatment session divided into five equal intramuscular injections of 4 Units each. The five injection sites are: two injections in each corrugator muscle and one injection in the procerus muscle.

Retreatment with Xeomin should be administered no more frequently than every three months.

Figure 3: Injection Sites for Glabellar Lines

Special Populations

The safety and effectiveness of Xeomin in the treatment of chronic sialorrhea, upper limb spasticity, cervical dystonia, blepharospasm, and glabellar lines in patients below 18 years of age have not been assessed [see Warnings and Precautions (5.1)].

Preparation and Reconstitution Technique

Prior to injection, reconstitute each vial of Xeomin with sterile, preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Form and Strengths (3)]. A 20-27 gauge short bevel needle is recommended for reconstitution. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 3 and [Dosage Form and Strengths (3)]). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then Xeomin must be discarded. Remove the syringe from the vial and mix Xeomin with the saline by carefully swirling and inverting/flipping the vial – do not shake vigorously. Reconstituted Xeomin is a clear, colorless solution free of particulate matter. Xeomin should not be used if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.

After reconstitution, Xeomin should be used for only one injection session and for only one patient. Reconstituted Xeomin solution should be administered within 24 hours after dilution. During this time period, unused reconstituted Xeomin may be stored in the original container in a refrigerator 2°C -8°C (36°F -46°F) for up to 24 hours until time of use. Xeomin vials are for single-dose only. Discard any unused portion.

Diluent volumes for reconstitution of Xeomin are indicated in Table 3.

Table 3: Diluent Volumes for Reconstitution of Xeomin
Volume of Preservative-free 0.9% Sodium Chloride Injection, USP	50 Unit Vial: Resulting dose in Units per 0.1 mL	100 Unit Vial: Resulting dose in Units per 0.1 mL	200 Unit Vial: Resulting dose in Units per 0.1 mL
0.25 mL	20 Units	-	-
0.5 mL	10 Units	20 Units	40 Units
1 mL	5 Units	10 Units	20 Units
1.25 mL	4 Units	8 Units	16 Units
2 mL	2.5 Units	5 Units	10 Units
2.5 mL	2 Units	4 Units	8 Units
4 mL	1.25 Units	2.5 Units	5 Units
5 mL	1 Unit	2 Units	4 Units

Administration

Reconstituted Xeomin is intended for intramuscular or intra-salivary gland injection only.

If proposed injection sites are marked with a pen, the product must not be injected through the pen marks; otherwise a permanent tattooing effect may occur.

For intramuscular injections, the number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted Xeomin injected.

Xeomin should be injected carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus. Before administering Xeomin, the physician should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.

Chronic Sialorrhea

A suitable sterile needle (e.g., 27-30 gauge (0.30-0.40 mm diameter), 12.5 mm length) should be used for intra-salivary gland administration for the treatment of chronic sialorrhea.

The salivary glands can be located using ultrasound imaging or surface anatomical landmarks [see Dosage and Administration (2.2)].

Upper Limb Spasticity and Cervical Dystonia

A suitable sterile needle (e.g., 26-gauge (0.45 mm diameter), 37 mm length for superficial muscles; or 22-gauge (0.70 mm diameter), 75 mm length for injections into deeper muscles) should be used in the intramuscular administration in the treatment of upper limb spasticity and cervical dystonia.

Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.

Blepharospasm

A suitable sterile needle (e.g., 30-gauge (0.40 mm diameter), 12.5 mm length) should be used in the intramuscular administration in the treatment of blepharospasm.

Glabellar Lines

A suitable sterile needle (e.g., 30-33 gauge (0.3-0.2 mm diameter), 13 mm length) should be used in the intramuscular administration in the treatment of glabellar lines.

Monitoring to Assess Effectiveness

The median first onset of Xeomin effect occurs within seven days after injection. The typical duration of effect of each treatment is up to 3 months; however, the effect may last significantly longer, or shorter, in individual patients.

Dosage Forms and Strengths

For injection: 50 Units, 100 Units, or 200 Units lyophilized powder in a single-dose vial for reconstitution only with preservative-free 0.9% Sodium Chloride Injection, USP.

ContraindicationsHypersensitivity

Hypersensitivity reactions have been reported with botulinum toxin products (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea). If serious and/or immediate hypersensitivity reactions occur further injection of Xeomin should be discontinued and appropriate medical therapy immediately instituted. The use of Xeomin in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction. Xeomin is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions (5.3)and Description (11)].

Infection at Injection Site

Use in patients with an infection at the injection site could lead to severe local or disseminated infection. Xeomin is contraindicated in the presence of infection at the proposed injection site(s).

Warnings and PrecautionsSpread of Toxin Effect

Postmarketing safety data from Xeomin and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to the spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can occur in adults treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.

Lack of Interchangeability between Botulinum Toxin Products

The potency Units of Xeomin are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of Xeomin cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Description (11)].

Dysphagia and Breathing Difficulties

Treatment with Xeomin and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved [See Warnings and Precautions (5.1)].

Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised.

Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products.

Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. In general, limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.

Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [See Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Patients with neuromuscular disorders with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of Xeomin.

Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated for Blepharospasm

Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Because of its anticholinergic effects, Xeomin should be used with caution in patients at risk of developing narrow angle glaucoma. To prevent ectropion, botulinum toxin products should not be injected into the medial lower eyelid area.

Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.

Risk of Ptosis in Patients Treated for Glabellar Lines

Do not exceed the recommended dosage and frequency of administration of Xeomin.

In order to reduce the complication of ptosis the following steps should be taken:

· Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.

· Corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

Human Albumin and Transmission of Viral Diseases

This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.

Adverse Reactions

The following adverse reactions to Xeomin are discussed in greater detail in other sections of the labeling:

· Spread of Effects from Toxin [see Warnings and Precautions (5.1)]

· Lack of Interchangeability between Botulinum Toxin Products [see Warnings and Precautions (5.2)]

· Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.3)]

· Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with Xeomin for Blepharospasm [see Warnings and Precautions (5.4)]

· Risk of Ptosis in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.5)]

· Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.6)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chronic Sialorrhea

Table 4 lists the adverse reactions that occurred in ≥3% of Xeomin-treated patients in the double-blind, placebo-controlled phase of the study in patients with chronic sialorrhea [see Clinical Studies (14.1)]. The most common adverse reactions (≥4%) were tooth extraction, dry mouth, diarrhea, and hypertension. In the controlled portion of this study, 74 patients received 100 Units of Xeomin and 36 patients received placebo. Xeomin-treated patients were 21-80 years old (mean 65 years), and were predominantly male (71%) and white (99.5%).

Table 4: Adverse Reactions (≥3%) and Greater for Xeomin than Placebo: Double-Blind Phase of the Placebo-Controlled Chronic Sialorrhea Study
Adverse Reaction	Xeomin 100 Units (N = 74) (%)	Placebo (N = 36) (%)
Tooth extraction	5	0
Dry mouth	4	0
Diarrhea	4	3
Hypertension	4	3
Fall	3	0
Bronchitis	3	0
Dysphonia	3	0
Back pain	3	0
Dry eye	3	0

Upper Limb Spasticity

Table 5 lists the most common (≥2%) adverse reactions following injection of Xeomin in two placebo-controlled, Phase 3 studies in patients with upper limb spasticity. Study 1 and Study 2 were both double-blind, placebo-controlled studies, with an open-label extension [see Clinical Studies (14.2)]. In the controlled portion of these studies, 283 patients received ≥120 Units to 400 Units, of which 217 patients received at least 400 units of Xeomin, and 182 patients received placebo. Xeomin-treated patients were 20-79 years old (mean 56 years), and were predominantly male (58%) and white (84%).

Table 5: Most Common Adverse Reactions (≥2%) and Greater for Xeomin than Placebo: Double-Blind Phase of Placebo-Controlled Upper Limb Spasticity Study 1 and Study 2
Adverse Reaction	Xeomin 400 Units (N = 217) (%)	Placebo (N = 182) (%)
Seizure	3	0
Nasopharyngitis	2	0
Dry mouth	2	1
Upper respiratory tract infection	2	1

Cervical Dystonia

The data described below reflect exposure to a single intramuscular dose of Xeomin in a placebo-controlled, Phase 3 trial in patients with cervical dystonia [see Clinical Studies (14.3)]. In this study, 159 patients received Xeomin (78 were randomized to receive a total dose of 120 Units, and 81 were randomized to receive a total dose of 240 Units). Xeomin-treated patients were 18 to 79 years old (mean 53 years), and were predominantly female (66%) and Caucasian (91%). At study baseline, approximately 25% had mild, 50% had moderate, and 25% had severe cervical dystonia. Approximately 61% of Xeomin-treated patients had previously received another botulinum toxin type A product. Common adverse events (≥5% in any Xeomin treatment group) observed in patients who received Xeomin (120 Units or 240 Units) included dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.

Table 6: Most Common Adverse Reactions (≥5%) and Greater than Placebo: Double-Blind Phase of Cervical Dystonia Clinical Trial
Adverse Reaction	Xeomin 120 Units (N=77) %	Xeomin 240 Units (N=82) %	Placebo (N=74) %
Any Adverse Reactions	57	55	42
Musculoskeletal and connective tissue disorders	23	32	11
Neck pain	7	15	4
Muscular weakness	7	11	1
Musculoskeletal pain	7	4	1
Gastrointestinal disorders	18	24	4
Dysphagia	13	18	3
Nervous system disorders	16	17	7
General disorders and administration site conditions	16	11	11
Injection site pain	9	4	7
Infections and infestations	14	13	11
Respiratory, thoracic and mediastinal disorders	13	10	3

Blepharospasm

In the placebo-controlled Phase 3 trial in patients with blepharospasm previously treated with onabotulinumtoxinA (Botox) [see Clinical Studies (14.4)], 74 patients received Xeomin at a mean dose of approximately 33 Units per eye (minimum 10 Units, maximum 50 Units). Xeomin-treated patients were 22 to 79 years of age (mean 62 years), predominantly female (65%), Caucasian (79%), and had a mean time since diagnosis of approximately 5 years.

The adverse events occurring in ≥5% of Xeomin-treated patients and greater than placebo in the Phase 3 study were eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection. No serious adverse events occurred in patients who received Xeomin; one placebo-treated patient experienced a serious adverse event (dyspnea).

Table 7: Most Common Adverse Reactions (≥5%) and Greater than Placebo: Double-Blind Phase of Blepharospasm Clinical Trial
Adverse Reaction	Xeomin (N=74) %	Placebo (N=34) %
* including vision blurred
Subjects with Adverse Reactions	70	62
Eye disorders	38	21
Eyelid ptosis	19	9
Dry eye	16	12
Visual impairment*	12	6
Gastrointestinal disorders	30	15
Dry mouth	16	3
Diarrhea	8	-
Infections and infestations	20	15
Nasopharyngitis	5	3
Respiratory tract infection	5	3
Nervous system disorders	14	9
Headache	7	3
General disorders and administration site conditions	11	9
Respiratory, thoracic and mediastinal disorders	11	3
Dyspnea	5	3

Glabellar Lines

In three placebo-controlled trials in 803 subjects with glabellar lines, 535 subjects received a single dose of 20 Units Xeomin and 268 subjects received placebo. Xeomin treated subjects were 24 to 74 years old, and were predominantly female (88%). The most frequent adverse reactions in Xeomin treated subjects were: headache 29 (5.4%), facial paresis 4 (0.7%), injection site hematoma 3 (0.6%) and eyelid edema 2 (0.4%). Four serious adverse events occurred in two placebo-treated subjects. Six Xeomin treated subjects experienced six serious adverse events. All serious adverse events were assessed as unrelated to study drug.

The adverse reactions below reflect exposure to Xeomin with glabellar lines in placebo-controlled studies. Adverse reactions are adverse events in which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 8: Adverse Reactions in Placebo-Controlled Glabellar Lines Trials
Adverse reactions	Xeomin (N=535) (%)	Placebo (N=268) (%)
Nervous system disorders	33 (6.1)	6 (2.2)
Headache1	29 (5.4)	6 (2.2)
Facial paresis (brow ptosis)	4 (0.7)	0
General disorders and administration site conditions	5 (0.9)	2 (0.7)
Injection site hematoma	3 (0.6)	0
Injection site pain	1 (0.2)	0
Facial pain	1 (0.2)	0
Injection site swelling	0	1 (0.4)
Sensation of pressure	0	1 (0.4)
Eye disorders	5 (0.9)	0
Eyelid edema	2 (0.4)	0
Blepharospasm	1 (0.2)	0
Eye disorder	1(0.2)	0
Eyelid ptosis	1(0.2)	0

In open label, multiple dose trials, adverse reactions were reported for 105 of the 800 subjects (13.1%). Headache was the most common adverse reaction, reported for 57 subjects (7.1%), followed by injection site hematoma in 8 subjects (1.0%). Adverse reactions reported in less than 1% of subjects were: facial paresis (brow ptosis), muscle disorder (elevation of eyebrow), injection site pain, and eyelid edema.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products in this class may be misleading.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Xeomin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: eye swelling, eyelid edema, dysphagia, nausea, flu-like symptoms, injection site pain, injection site reaction, allergic dermatitis, localized allergic reactions like swelling, edema, erythema, pruritus or rash, herpes zoster, muscular weakness, muscle spasm, dysarthria, myalgia and hypersensitivity.

Drug Interactions

No formal drug interaction studies have been conducted with Xeomin.

Co-administration of Xeomin and aminoglycoside antibiotics or other agents interfering with neuromuscular transmission, e.g., tubocurarine-type muscle relaxants, should only be performed with caution as these agents may potentiate the effect of the toxin. Use of anticholinergic drugs after administration of Xeomin may potentiate systemic anticholinergic effects.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of Xeomin.

USE IN SPECIFIC POPULATIONSPregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of Xeomin in pregnant women. Xeomin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Xeomin was embryotoxic in rats and increased abortions in rabbits when given at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 Units), on a body weight basis.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

When Xeomin was administered intramuscularly to pregnant rats during organogenesis (3 Units/kg, 10 Units/kg, or 30 Units/kg on gestational days [GDs] 6, 12, and 19; or 7 Units/kg on GDs 6 to 19; or 2 Units/kg, 6 Units/kg, or 18 Units/kg on GDs 6, 9, 12, 16, and 19), decreases in fetal body weight and skeletal ossification were observed at doses that were also maternally toxic. The no-effect level for embryotoxicity in rats was 6 Units/kg (3 times the MRHD for cervical dystonia on a body weight basis). Intramuscular administration to pregnant rabbits during organogenesis (1.25 Units/kg, 2.5 Units/kg, or 5.0 Units/kg on GDs 6, 18, and 28) resulted in an increased rate of abortion at the highest dose, which was also maternally toxic. In rabbits, the no-effect level for increased abortion was 2.5 Units/kg (similar to the MRHD for cervical dystonia on a body weight basis).

Lactation

Risk Summary

There are no data on the presence of Xeomin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Xeomin and any potential adverse effects on the breastfed infant from Xeomin or from the underlying maternal conditions.

Pediatric Use

Safety and effectiveness of Xeomin in patients less than 18 years of age have not been established [see Warnings and Precautions (5.1)].

Geriatric Use

Chronic Sialorrhea

Of the 184 patients in the placebo-controlled study in chronic sialorrhea [see Clinical Studies (14.1)], 107 (58%) were 65 years of age and over, including 17 of the 36 patients (47%) who received placebo, and 46 of the 74 patients (62%) treated with Xeomin 100 Units. No differences in safety or effectiveness were observed between older and younger patients. Other clinical studies have not identified differences in responses between older and younger patients, but increased sensitivity in older patients cannot be ruled out.

Upper Limb Spasticity

Of the total number of 283 patients treated with Xeomin in placebo-controlled studies in upper limb spasticity, 70 patients were 65 years of age and over, and 7 patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between older and younger patients. Other clinical studies have not identified differences in responses between older and younger patients, but increased sensitivity in older patients cannot be ruled out.

Cervical Dystonia

In the placebo-controlled study in cervical dystonia [see Clinical Studies (14.3)], 29 patients were older than 65 years of age, including 19 patients who received Xeomin and 10 patients who received placebo. Of these, ten (53%) Xeomin-treated patients and four (40%) placebo-treated patients experienced an adverse event. For patients over 65 years of age treated with Xeomin, the most common adverse events were dysphagia (4 patients, 21%) and asthenia (2 patients, 11%). One Xeomin-treated patient (5%) experienced severe dizziness.

Blepharospasm

In the placebo-controlled study in blepharospasm [see Clinical Studies (14.4)], 41 patients were older than 65 years of age, including 29 of 75 patients (39%) who received Xeomin and 12 of 34 patients (35%) who received placebo. Of these patients, 22 of 29 (76%) Xeomin-treated patients, compared with 7 of 12 (58%) placebo-treated patients, experienced an adverse event. One Xeomin-treated patient experienced severe dysphagia.

Glabellar Lines

There are limited clinical data with Xeomin in subjects over 65 years of age and over in clinical studies with glabellar lines. Of the total number of subjects in the placebo-controlled clinical studies GL1 and GL2, 21 (4%) subjects were 65 and over. Efficacy was observed in 20% (3/15) of Xeomin subjects 65 years and over. For the entire safety database of geriatric subjects, there was no increase in the incidence of adverse events related to treatment with Xeomin.

Overdosage

Excessive doses of Xeomin may be expected to produce neuromuscular weakness with a variety of symptoms, particularly when treated intramuscularly. Respiratory support may be required where excessive doses cause paralysis of the respiratory muscles. In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis [See Warnings and Precautions (5.1, 5.3)]. Symptomatic treatment may be necessary.

Symptoms of overdose are not likely to be present immediately following injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for several weeks for signs and symptoms of excessive muscle weakness or paralysis.

There is no significant information regarding overdose from clinical studies of Xeomin.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 770-488-7100. More information can be obtained at http://www.cdc.gov/ncidod/srp/drugs/formulary.html#1a.

Xeomin Description

The active ingredient of Xeomin is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is separated from the proteins (hemagglutinins and non-hemagglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins. Xeomin is a sterile white to off-white lyophilized powder intended for intramuscular or intra-salivary gland injection after reconstitution with preservative-free 0.9% Sodium Chloride Injection, USP (3). One vial of Xeomin contains 50 Units, 100 Units, or 200 Units of incobotulinumtoxinA, human albumin (1 mg), and sucrose (4.7 mg).

The primary release procedure for Xeomin uses a cell-based potency assay to determine the potency relative to a reference standard. One Unit corresponds to the median intraperitoneal lethal dose (LD50) in mice. As the method for conducting the assay is specific to Xeomin, Units of biological activity of Xeomin cannot be converted into Units of any other botulinum toxin assessed with other specific assays.

Xeomin - Clinical PharmacologyMechanism of Action

Xeomin blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

Pharmacodynamics

The return of increased muscle tone following injection typically occurs within 3 to 4 months.

Pharmacokinetics

General characteristics of the active substance:

Using currently available analytical technology, it is not possible to detect Xeomin in the peripheral blood following intramuscular or intraglandular injection at the recommended doses.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies to evaluate the carcinogenic potential of Xeomin have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted for Xeomin.

Impairment of Fertility

In a fertility and early embryonic development study in rabbits, males and females were dosed with Xeomin (1.25 Units/kg, 2.5 Units/kg, or 3.5 Units/kg) intramuscularly every two weeks for 5 and 3 doses, respectively, beginning 2 weeks prior to mating. No effects on mating or fertility were observed. The highest dose tested is approximately twice the maximum recommended human dose for cervical dystonia (120 Units) on a body weight basis.

Clinical StudiesChronic Sialorrhea

The efficacy and safety of Xeomin for the treatment of chronic sialorrhea were evaluated in a double-blind, placebo-controlled clinical trial that enrolled a total of 184 patients with chronic sialorrhea resulting from Parkinson's disease, atypical parkinsonism, stroke, or traumatic brain injury, that was present for at least three months. Patients with a history of aspiration pneumonia, amyotrophic lateral sclerosis, salivary gland or duct malformation, and gastroesophageal reflux disease were excluded. The study consisted of a 16-week main phase, followed by an extension period of dose-blinded treatment with Xeomin.

In the main phase, a fixed total dose of Xeomin (100 Units or 75 Units) or placebo was administered into the parotid and submandibular salivary glands in a 3:2 dose ratio. The co-primary efficacy variables were the change in unstimulated Salivary Flow Rate (uSFR, Table 9) and the change in Global Impression of Change Scale (GICS, Table 10) at Week 4 post-injection. A total of 173 treated patients completed the main phase of the study. For both the uSFR and GICS, Xeomin 100 Units was significantly better than placebo (see Table 9 and Table 10). Xeomin 75 Units was not significantly better than placebo.

Table 9: Change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase
	Xeomin 100 Units	Placebo
	N = 73	N=36
* p=0.004
*Week 4	-0.13	-0.04
Week 8	-0.13	-0.02
Week 12	-0.12	-0.03
Week 16	-0.11	-0.01
Table 10: Mean GICS at Week 4, 8, 12, and 16 of Main Phase
	Xeomin 100 Units	Placebo
	N = 74	N=36
* p=0.002
*Week 4	1.25	0.67
Week 8	1.30	0.47
Week 12	1.21	0.56
Week 16	0.93	0.41

In the extension period, patients received up to 3 additional treatments with Xeomin 100 Units or 75 Units every 16±2 weeks, for a total exposure duration of up to 64 weeks. Patients had periodic dental examinations to monitor for changes in dentition and oral mucosa. A total of 151 patients completed the extension period.

Upper Limb Spasticity

The efficacy and safety of Xeomin for the treatment of upper limb spasticity were evaluated in two Phase 3, randomized, multi-center, double-blind studies.

Study 1 and Study 2 were both prospective, double-blind, placebo-controlled, randomized, multi-center trials with an open-label extension period (OLEX) to investigate the efficacy and safety of Xeomin in the treatment of post-stroke spasticity of the upper limb. For patients who had previously received botulinum toxin treatment in any body region, Study 1 and Study 2 required that ≥ 12 months and ≥ 4 months, respectively, had passed since the most recent botulinum toxin administration.

Study 1 consisted of a 12-week main phase followed by three 12-week OLEX treatment cycles for a total exposure duration of 48 weeks. The study included 317 treatment-naïve patients who were at least three months post-stroke in the main study period (210 Xeomin and 107 placebo). During the main period, Xeomin (fixed total dose of 400 Units) and placebo were administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups. 296 treated patients completed the main phase and participated in the first OLEX cycle. Each OLEX cycle consisted of a single treatment session (Xeomin 400 Units total dose, distributed among all affected muscles) followed by a 12 week observation period.

Study 2 consisted of a 12 - 20 week main phase followed by an OLEX period of 48 – 69 weeks for up to 89 weeks of exposure to Xeomin. The study included 148 treatment-naïve and pre-treated patients with a confirmed diagnosis of post-stroke spasticity of the upper limb who were at least six months post-stroke (73 Xeomin and 75 placebo). During the main period, for each patient, the clinical patterns of flexed wrist and clenched fist were treated with fixed doses (90 Units and 80 Units, respectively). Additionally, if other upper limb spasticity patterns were present, the elbow, forearm and thumb muscles could be treated with fixed doses of Xeomin per muscle. 145 patients completed the main phase and participated in the OLEX period, during which time the dosing of each involved muscle could be adapted individually. During the main and OLEX periods, the maximum total dose per treatment session and 12-week interval was 400 Units.

The average Xeomin doses injected into specific muscles and the number of injection sites per muscle in Study 1 and Study 2 are presented in Table 11.

Table 11: Doses Administered to Individual Muscles (Main Period) in Study 1 and Study 2 Intent to Treat (ITT)
Muscle Group	Muscle	Study 1 Units Injected	Injection Site Per Muscle	Study 2 Units Injected	Injection Site Per Muscle
		Xeomin N=210 Mean±SD	Xeomin Median (Min; Max)	Xeomin N=73 Mean±SD	Xeomin Median (Min; Max)
All	Overall	400 ± 2 Units	--	307 ± 77 Units	--
Elbow flexors	Overall	151 ± 50 Units	5 (1; 11)	142 ± 30 Units	5 (2; 9)
	Biceps	90 ± 21 Units	3 (1; 4)	80 ± 0 Units	3 (2; 4)
	Brachialis	52 ± 26 Units	2 (1; 4)	50 ± 0 Units	2 (1; 2)
	Brachioradialis	43 ± 16 Units	2 (1; 3)	60 ± 2 Units	2 (1; 3)
Wrist flexors	Overall	112 ± 43 Units	4 (1; 6)	90 ± 0 Units	4 (4; 4)
	Flexor carpi radialis	58 ± 22 Units	2 (1; 3)	50 ± 0 Units	2 (2; 2)
	Flexor carpi ulnaris	56 ± 22 Units	2 (1; 3)	40 ± 0 Units	2 (2; 2)
Finger flexors	Overall	104 ± 35 Units	4 (1; 4)	80 ± 0 Units	4 (4; 4)
	Flexor digitorum profundus	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
	Flexor digitorum superficialis	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
Forearm pronators	Overall	52 ± 24 Units	2 (1; 3)	47 ± 16 Units	2 (1; 3)
	Pronator quadratus	26 ± 13 Units	1 (1; 1)	25 ± 0 Units	1 (1; 1)
	Pronator teres	42 ± 13 Units	1 (1; 2)	40 ± 0 Units	1.5 (1; 2)
Thumb flexors/adductors	Overall	37 ± 25 Units	2 (1; 4)	25 ± 10 Units	1.5 (1; 3)
	Adductor pollicis	14 ± 8 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis brevis / opponens pollicis	14 ± 9 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis longus	26 ± 16 Units	1 (1; 2)	20 ± 0 Units	1 (1; 1)

In Study 1, the primary efficacy variable was the change from baseline in Ashworth Scale (AS) score of the primary target clinical pattern determined by the investigator at the Week 4 visit. The Ashworth Scale is a clinical measure of the severity of spasticity by judging resistance to passive movement. The spasticity of the elbow flexors, wrist flexors, finger flexors, and thumb muscles as well as the forearm pronators was assessed on the 0 to 4-point Ashworth scale at each visit.

Table 12: Efficacy Results by Patterns of Spasticity in Study 1, Week 4
	Mean Change in Ashworth Scale
	Xeomin N=171	Placebo N=88
The analysis is based on Last Observation Carried Forward in the Intent To Treat population. p<0.001
Total Primary Target Clinical Pattern (flexed wrist, flexed elbow, and clenched fist)	-0.9	-0.5

The co-primary efficacy variable of Study 1 was the Investigator's Global Impression of Change Scales (GICS) after 4 Weeks of treatment with Xeomin or placebo. The GICS is a global measure of a subject's functional improvement. Investigators were asked to evaluate the subject's global change in spasticity of the upper limb due to treatment, compared to the condition before the last injection. The response was assessed using a 7-point Likert scale that ranges from –3 (very much worse) to +3 (very much improved). A greater percentage of Xeomin-treated subjects (43%) than placebo-treated subjects (23%) reported 'very much improved' and 'much improved' in their spasticity (see Figure 4).

Figure 4: Investigator's GICS in Study 1

Xeomin was considered to be superior to placebo in Study 1 only if statistical significance was reached in both the AS and GICS variables.

Cervical Dystonia

Xeomin has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥20, TWSTRS severity score ≥10, TWSTRS disability score ≥3, and TWSTRS pain score ≥1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of Xeomin 240 Units (n=81), Xeomin 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (Xeomin 240 Units, Xeomin 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 13 indicates the average Xeomin dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.

Table 13: Xeomin 120 Units Initial Dose (Units and % of the Total Dose) by Unilateral Muscle Injected During Double Blind Pivotal Phase 3 Study
		Xeomin Dose Injected
	Number of Patients Injected Per Muscle	Median Xeomin Units	75th percentile Xeomin Units
Sternocleidomastoid	63	25	35
Splenius capitis/ Semispinalis capitis	78	48	63
Trapezius	55	25	38
Levator scapulae	49	25	25
Scalenus (medius and anterior)	27	20	25

Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.

The mean age of the study patients was 53 years, and 66% of the patients were women. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.

The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. In the ITT population, the difference between the Xeomin 240 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -9.0 points, 95% confidence interval (CI) -12.0; -5.9 points; the difference between the Xeomin 120 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -7.5 points, 95% CI -10.4; -4.6 points.

Figure 5 illustrates the cumulative percentage of patients from each of the three treatment groups who had attained the specified change in TWSTRS Score from baseline versus 4 weeks post-injection. Three change scores have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown.

Figure 5: Cumulative Percentage of Patients with Specified Changes from Baseline TWSTRS Total Score at Week 4

The curves demonstrate that both patients assigned to placebo and Xeomin have a wide range of responses, but that the active treatment groups are more likely to show greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.

Comparison of each Xeomin group to the placebo group was statistically significant at p<0.001. Initial Xeomin doses of 120 Units and 240 Units demonstrated no significant difference in effectiveness between the doses. The efficacy of Xeomin was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.

Examination of age and gender subgroups did not identify differences in response to Xeomin among these subgroups. There were too few African-American patients to adequately assess efficacy in that population.

Blepharospasm

Xeomin has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 109 patients with blepharospasm. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline Jankovic Rating Scale (JRS) Severity subscore ≥2, and a stable satisfactory therapeutic response to previous administrations of onabotulinumtoxinA (Botox). At least 10 weeks had to have elapsed since the most recent onabotulinumtoxinA administration. Patients with any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (2:1) to receive a single administration of Xeomin (n=75) or placebo (n=34). Each patient in the Xeomin group received a Xeomin treatment (dose, volume, dilution, and injection sites per muscle) that was similar to the most recent onabotulinumtoxinA injection sessions prior to study entry. The highest dose permitted in this study was 50 Units per eye; the mean Xeomin dose was 33 Units per eye.

In Table 14 the most frequently injected sites, the median dose per injection site, and the median number (and range) of injection sites per eye are presented.

Table 14: Median Dose and Median Number of Injection Sites per Eye (Blepharospasm)
Injection Area	Median Units Xeomin	Median Number of Injection Sites (Min-Max)
Temporal Area	13	2 (1 – 6)
Eyebrow Area	5	1 (1 – 4)
Upper Lid Area	10	2 (1 – 4)
Lower Lid Area	8	2 (1 – 3)
Orbital Rim	5	1 (1 – 3)

Patients were assessed during clinic visits at Weeks 3 and 6, and then by telephone or at clinic visits every two weeks up to Week 20.

The mean age of the study patients was 62 years, and 65% of the patients were women. The study was completed by 94% of study patients. Approximately one third of patients had other dystonic phenomena; in all but 1% this was limited to facial, cervical, perioral and mandibular muscles. No patients discontinued the study prematurely due to adverse events.

The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's most recent value (i.e., last observation carried forward). In the ITT population, the difference between the Xeomin group and the placebo group in the change of the JRS Severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points. Comparison of the Xeomin group to the placebo group was statistically significant at p<0.001.

Figure 6: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6

Examination of age and gender subgroups did not identify substantial differences in response to Xeomin among these subgroups. There were too few African-American patients to assess efficacy in that population.

Glabellar Lines

Two identically designed randomized, double-blind, multi-center, placebo controlled clinical trials (Studies GL-1 and GL-2) were conducted to evaluate Xeomin for use in the temporary improvement of moderate to severe glabellar lines. The studies enrolled 547 healthy patients (≥18 years old) with glabellar lines of at least moderate severity at maximum frown. Three hundred sixty six subjects were treated with 20 Units of Xeomin and 181 subjects were treated with placebo. Subjects were excluded if they had marked ptosis, deep dermal scarring, or an inability to lessen glabellar lines, even by physically spreading them apart. The mean age of study subjects was 46 years. The majority of patients were female (86% and 93% in Studies GL-1 and GL-2, respectively), and predominantly Caucasian (89% and 65% respectively). The study subjects received either 20 Units of Xeomin or an equal amount of placebo. The total dose was delivered in 5 equally divided intramuscular injections of 4 Units each to specific sites (see Figure 3). Subjects were followed up for 120 days.

Investigators and subjects assessed efficacy at maximum frown on Day 30 of treatment using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Composite treatment success was defined as a 2-grade improvement on this scale compared to baseline for both the investigator's and subject's assessments on Day 30. The percentage of subjects with treatment success was greater on the Xeomin arm than the placebo arm at Day 30 in both studies (see Table 15). The percentage of subjects with composite treatment success at each visit are presented in Figure 7.

Table 15: Treatment Success at Day 30 (at Least 2 Grades Improvement from Baseline at Maximum Frown)
	GL-1		GL-2
	Xeomin (N=184)	Placebo (N=92)	Xeomin (N=182)	Placebo (N=89)
* Success on both the Investigator and Subject Assessments
Composite Treatment Success*	111 (60%)	0 (0%)	87 (48%)	0 (0%)
Investigator Assessment	141 (77%)	0 (0%)	129 (71%)	0 (0%)
Subject Assessment	120 (65%)	0 (0%)	101 (55%)	1 (1%)

Figure 7: Percentage of Subjects with Composite Treatment Success by Visit – Observed Cases (GL-1 and GL-2)

How Supplied/Storage and HandlingHow Supplied

Xeomin (incobotulinumtoxinA) for injection is a sterile white to off-white lyophilized powder supplied in Type 1 borosilicate glass single-dose vials with tamper-proof aluminum seals and bromobutyl rubber closures that are not made with natural rubber latex in the following pack sizes:

Chronic Sialorrhea, Upper Limb Spasticity, and Cervical Dystonia

Package	Xeomin 50 Units	Xeomin 100 Units	Xeomin 200 Units
single vial pack	NDC 0259-1605-01	NDC 0259-1610-01	NDC 0259-1620-01

Blepharospasm

Package	Xeomin 50 Units	Xeomin 100 Units
single vial pack	NDC 0259-1605-01	NDC 0259-1610-01

Glabellar Lines

Package	Xeomin 50 Units	Xeomin 100 Units
single vial pack	NDC 46783-161-01	NDC 46783-160-01

Storage

Unopened vials of Xeomin can be stored at room temperature 20°C to 25°C (68°F to 77°F), in a refrigerator at 2°C to 8°C (36°F to 46°F), or a freezer at -20°C to -10°C (-4°F to 14°F). Do not use after the expiration date on the vial.

Handling

Xeomin is reconstituted prior to use with sterile preservative-free 0.9% Sodium Chloride Injection, USP and may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours until time of use [see Dosage and Administration (2.8)].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Provide a copy of the Medication Guide and review the contents with the patient.

General

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.

Previously immobile or sedentary patients should be reminded to gradually resume activities following the injection of Xeomin.

Patients should be informed that injections of Xeomin may cause dyspnea, or mild to severe dysphagia, with the risk of aspiration [see Boxed Warning and Warnings and Precautions (5.1, 5.3)].

Patients should be counseled that if loss of strength, muscle weakness, blurred vision, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities.

Patients should be informed that injections of Xeomin may cause reduced blinking or effectiveness of blinking, and that they should seek immediate medical attention if eye pain or irritation occurs following treatment.

Manufactured by:
Merz Pharmaceuticals GmbH
Eckenheimer Landstrasse 100
Frankfurt Germany
U.S. License Number 1830

Distributed by:
Merz Pharmaceuticals, LLC
6501 Six Forks Road
Raleigh, NC 27615

and

Merz North America, Inc.
4133 Courtney Street, Suite 10
Franksville, WI 53126

© 2018 Merz Pharmaceuticals, LLC

Xeomin® is a registered trademark of Merz Pharma GmbH & Co KGaA.

Botox® is a registered trademark of Allergan, Inc.

This Medication Guide has been approved by the U. S. Food and Drug Administration.				Revised: 7/2018
MEDICATION GUIDE Xeomin® (Zeo-min) (incobotulinumtoxinA) for injection, for intramuscular or intraglandular use
What is the most important information I should know about Xeomin? Xeomin may cause serious side effects that can be life-threatening. Call your doctor or get medical help right away if you have any of these problems after treatment with Xeomin: · Problems with swallowing, speaking, or breathing. These problems can happen hours to weeks after an injection of Xeomin if the muscles that you use to breathe and swallow become weak after the injection. Death can happen as a complication if you have severe problems with swallowing or breathing after treatment with Xeomin. o People with certain breathing problems may need to use muscles in their neck to help them breathe. These people may be at greater risk for serious breathing problems with Xeomin. o Swallowing problems may last for several months. People who cannot swallow well may need a feeding tube to receive food and water. If swallowing problems are severe, food or liquids may go into your lungs. People who already have swallowing or breathing problems before receiving Xeomin have the highest risk of getting these problems. · Spread of toxin effects. In some cases, the effect of botulinum toxin may affect areas of the body away from the injection site and cause symptoms of a serious condition called botulism. The symptoms of botulism include:
	loss of strength and muscle weakness all over the body double vision blurred vision and drooping eyelids hoarseness or change or loss of voice		trouble saying words clearly loss of bladder control trouble breathing trouble swallowing
These symptoms can happen hours to weeks after you receive an injection of Xeomin.. These problems could make it unsafe for you to drive a car or do other dangerous activities. See "What should I avoid while receiving Xeomin?"
What is Xeomin? Xeomin is a prescription medicine used in adults: · that is injected into glands that make saliva and is used to treat long-lasting (chronic) drooling (sialorrhea). · that is injected into muscles and used to: o treat increased muscle stiffness in the arm because of upper limb spasticity. o treat the abnormal head position and neck pain with cervical dystonia (CD) in adults who have and have not had prior treatment with botulinum toxin. o treat abnormal spasm of the eyelids (blepharospasm) in adults who have had prior treatment with onabotulinumtoxinA (BOTOX). o improve the look of moderate to severe frown lines between the eyebrows (glabellar lines) for a short period of time (temporary). It is not known if Xeomin is safe and effective in children under 18 years of age.
Do not take Xeomin if you: · are allergic to Xeomin or any of the ingredients in Xeomin. See the end of this Medication Guide for a list of ingredients in Xeomin. · had an allergic reaction to any other botulinum toxin products such as rimabotulinumtoxinB (MYOBLOC), onabotulinumtoxinA (BOTOX, BOTOX COSMETIC), or abobotulinumtoxinA (DYSPORT). · have a skin infection at the planned injection site.
Before receiving Xeomin, tell your doctor about all of your medical conditions, including if you: · have a disease that affects your muscles and nerves (such as amyotrophic lateral sclerosis [ALS or Lou Gehrig's disease], myasthenia gravis or Lambert-Eaton syndrome). See "What is the most important information I should know about Xeomin?" · have had any side effect from any other botulinum toxin in the past. · have a breathing problem, such as asthma or emphysema. · have a history of swallowing problems or inhaling food or fluid into your lungs (aspiration). · have bleeding problems. · have drooping eyelids. · plan to have surgery. · have had surgery on your face. · are pregnant or plan to become pregnant. It is not known if Xeomin can harm your unborn baby. · are breastfeeding or plan to breastfeed. It is not known if Xeomin passes into your breast milk. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Talk to your doctor before you take any new medicines after you receive Xeomin. Using Xeomin with certain other medicines may cause serious side effects. Do not start any new medicines until you have told your doctor that you have received Xeomin in the past. Especially tell your doctor if you: · have received any other botulinum toxin product in the last four months. · have received injections of botulinum toxin such as rimabotulinumtoxinB (MYOBLOC), onabotulinumtoxinA (BOTOX, BOTOX COSMETIC) or abobotulinumtoxinA (DYSPORT) in the past. Be sure your doctor knows exactly which product you received. The dose of Xeomin may be different from other botulinum toxin products that you have received. · have recently received an antibiotic by injection or inhalation. · take muscle relaxants. · take an allergy or cold medicine. · take a sleep medicine. Ask your doctor if you are not sure if you take any of the medicines listed above. Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.
How will I receive Xeomin? · Xeomin is a shot (injection) that your doctor will give you. · Xeomin is injected into your affected muscles or glands. · Your doctor may change your dose of Xeomin during treatment.
What should I avoid while taking Xeomin? Xeomin may cause loss of strength or general muscle weakness, blurred vision, or drooping eyelids within hours to weeks of taking Xeomin. If this happens, do not drive a car, operate machinery, or do other dangerous activities. See "What is the most important information I should know about Xeomin? "
What are the possible side effects of Xeomin? Xeomin may cause serious side effects, including: See "What is the most important information I should know about Xeomin?" · Injury to the cornea (the clear front surface of the eye) in people treated for blepharospasm. People who receive Xeomin to treat spasm of the eyelid may have reduced blinking that can cause a sore on their cornea or other problems of the cornea. Call your healthcare provider or get medical care right away if you have eye pain or irritation after treatment with Xeomin. · Xeomin may cause other serious side effects including allergic reactions. Symptoms of an allergic reaction to Xeomin may include: itching, rash, redness, swelling, wheezing, trouble breathing, or dizziness or feeling faint. Tell your doctor or get medical help right away if you get wheezing or trouble breathing, or if you get dizzy or faint. The most common side effects of Xeomin in people with chronic sialorrhea include:
	· needing to have a tooth pulled (extracted) · dry mouth	· diarrhea · high blood pressure
The most common side effects of Xeomin in people with upper limb spasticity include:
	· seizure · nasal congestion, sore throat and runny nose	· dry mouth · upper respiratory infection
The most common side effects of Xeomin in people with cervical dystonia include:
	· difficulty swallowing · neck pain · muscle weakness	· pain at the injection site · muscle and bone pain
The most common side effects of Xeomin in people with blepharospasm include:
	· drooping of the eyelid · dry eye · dry mouth · diarrhea · headache	· vision problems · shortness of breath · nasal congestion, sore throat, and runny nose · respiratory infection
The most common side effect of Xeomin in people with glabellar lines include:
	· headache
These are not all the possible side effects of Xeomin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Xeomin. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about Xeomin that is written for health professionals.
What are the ingredients in Xeomin? Active ingredient: botulinum toxin type A Inactive ingredients: human albumin and sucrose Manufactured by: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, Frankfurt Germany U.S. License Number 1830 Distributed by: Merz Pharmaceuticals, LLC, 6501 Six Forks Road, Raleigh, NC 27615 and Merz North America, Inc. 4133 Courtney Road, Suite 10, Franksville, WI 53126 Merz Pharmaceuticals, LLC, Xeomin® is a registered trademark of Merz Pharma GmbH & Co KGaA. Botox®, Botox® Cosmetic, Dysport®, and Myobloc® are registered trademarks of their respective owners. EM00674-03

PRINCIPAL DISPLAY PANEL - 50 Unit Vial Carton

1 vial
Rx Only
NDC 0259-1605-01

incobotulinumtoxinA

Xeomin®
for Injection

For Intramuscular
and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are
not interchangeable between commercial products.

MERZ

Dispense the enclosed Medication
Guide to each patient.

PRINCIPAL DISPLAY PANEL - 100 Unit Vial Carton

1 vial
Rx Only
NDC 0259-1610-01

incobotulinumtoxinA

Xeomin®
for Injection

For Intramuscular
and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are
not interchangeable between commercial products.

MERZ

Dispense the enclosed Medication
Guide to each patient.

PRINCIPAL DISPLAY PANEL - 50 Unit Vial Carton - NDC 0259-4150-01

1 vial
Rx Only
NDC 0259-4150-01

incobotulinumtoxinA

Xeomin®
for Injection

For Intramuscular
and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are
not interchangeable between commercial products.

MERZ

Dispense the enclosed Medication
Guide to each patient.

PRINCIPAL DISPLAY PANEL - 100 Unit Vial Carton - NDC 0259-4110-01

1 vial
Rx Only
NDC 0259-4110-01

incobotulinumtoxinA

Xeomin®
for Injection

For Intramuscular
and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are
not interchangeable between commercial products.

MERZ

Dispense the enclosed Medication
Guide to each patient.

PRINCIPAL DISPLAY PANEL - 200 Unit Vial Carton

1 vial
Rx Only
NDC 0259-1620-01

incobotulinumtoxinA

Xeomin®
for Injection

For Intramuscular
and Intraglandular Use

WARNING: Dosing Units of botulinum toxins are
not interchangeable between commercial products.

MERZ

Dispense the enclosed Medication
Guide to each patient.

Xeomin incobotulinumtoxina injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0259-1605 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Botulinum Toxin Type A (Botulinum Toxin Type A) Botulinum Toxin Type A 50 [USP'U]

Inactive Ingredients Ingredient Name Strength Albumin Human   Sucrose

Packaging # Item Code Package Description   1 NDC:0259-1605-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125360 09/01/2010

Xeomin incobotulinumtoxina injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0259-1610 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Botulinum Toxin Type A (Botulinum Toxin Type A) Botulinum Toxin Type A 100 [USP'U]

Inactive Ingredients Ingredient Name Strength Albumin Human   Sucrose

Packaging # Item Code Package Description   1 NDC:0259-1610-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125360 09/01/2010

Xeomin incobotulinumtoxina injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0259-4150 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Botulinum Toxin Type A (Botulinum Toxin Type A) Botulinum Toxin Type A 50 [USP'U]

Inactive Ingredients Ingredient Name Strength Albumin Human   Sucrose

Packaging # Item Code Package Description   1 NDC:0259-4150-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125360 09/01/2010

Xeomin incobotulinumtoxina injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0259-4110 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Botulinum Toxin Type A (Botulinum Toxin Type A) Botulinum Toxin Type A 100 [USP'U]

Inactive Ingredients Ingredient Name Strength Albumin Human   Sucrose

Packaging # Item Code Package Description   1 NDC:0259-4110-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125360 09/01/2010

Xeomin incobotulinumtoxina injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0259-1620 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Botulinum Toxin Type A (Botulinum Toxin Type A) Botulinum Toxin Type A 200 [USP'U]

Inactive Ingredients Ingredient Name Strength Albumin Human   Sucrose

Packaging # Item Code Package Description   1 NDC:0259-1620-01 1 VIAL, SINGLE-USE in 1 CARTON   1   200 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE   2 NDC:0259-1620-10 1 VIAL, SINGLE-USE in 1 CARTON   2   200 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125360 11/20/2015

Labeler - Merz Pharmaceuticals, LLC (126209282)

Establishment
Name	Address	ID/FEI	Operations
Merz Pharma GmbH & Co. KGaA		342543051	MANUFACTURE(0259-1605, 0259-1610, 0259-4150, 0259-4110, 0259-1620)

 

Merz Pharmaceuticals, LLC